title: Evidence of intravenous immunoglobulin as a critical supportive therapy against Clostridium difficile toxin-mediated lethality in mice.
abstract: OBJECTIVE
  Clostridium difficile produces toxins and is an aetiological organism of pseudomembranous colitis. Immunoglobulin is one of the treatment strategies against fulminant C. difficile infections, but the clinical evidence is still limited. We examined the efficacy of intravenous immunoglobulin (IVIg) in C. difficile toxin (CDT)-mediated lethality and cellular injury in mice.
  
  
  METHODS
  Mice were intraperitoneally injected with 0.2 mL of filter-sterilized C. difficile culture supernatant (CDT preparation). The IVIg preparation was intravenously administered at several timepoints. We also examined alteration of intestinal permeability and an apoptosis marker in the gut. In in vitro experiments, HEp-2 cells were incubated with a CDT preparation in the presence or absence of the IVIg preparation, after which cell viability and lactate dehydrogenase release were examined.
  
  
  RESULTS
  All control mice died by day 2 after injection of the CDT preparation. The maximum effects of IVIg (100% survival) were observed when the mice were treated with IVIg at the same time as injection of the CDT preparation. The IVIg effects were closely associated with improvement of intestinal vascular permeability and mucosal damage in the gut. In addition, reduction of an apoptosis marker (histone-associated DNA fragments) was demonstrated in the mice treated with IVIg. Interestingly, a smaller increase in histone-associated DNA fragments was observed in FasL-deficient mice treated with the CDT preparation compared with wild-type.
  
  
  CONCLUSIONS
  These data demonstrated that IVIg may be protective against CDT-mediated lethality, when administered at the appropriate time. The present data also suggest an increase in intestinal permeability, probably through exaggeration of Fas/FasL-mediated apoptosis, as a key mechanism of C. difficile-mediated diseases.
authors.affiliation: Department of Microbiology and Infectious Diseases, Toho University Faculty of Medicine, Tokyo, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Saito
authors.forename: Soichiro
authors.initials: S
authors.lastname: Kimura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tateda
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Mori
authors.forename: Natsue
authors.initials: N
authors.lastname: Hosono
authors.forename: Kayoko
authors.initials: K
authors.lastname: Hayakawa
authors.forename: Yoshikiyo
authors.initials: Y
authors.lastname: Akasaka
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Ishii
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Sumiyama
authors.forename: Shinya
authors.initials: S
authors.lastname: Kusachi
authors.forename: Jiro
authors.initials: J
authors.lastname: Nagao
authors.forename: Keizo
authors.initials: K
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D000992:Antitoxins / Q000008:administration & dosage*; D002460:Cell Line / Q000187:drug effects; D002470:Cell Survival; D016360:Clostridioides difficile / Q000472:pathogenicity*; D003015:Clostridium Infections / Q000401:mortality / Q000628:therapy*; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage*; D007167:Immunotherapy / Q000379:methods; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000992:Antitoxins; D016756:Immunoglobulins, Intravenous; D007770:L-Lactate Dehydrogenase